First row transition metal catalysts show potential as cheaper, more abundant alternatives to their second and third row counterparts. However, catalysis with first-row transition metal systems is frequently hampered by low turnover and sensitivity to catalyst poisoning, often necessitating higher catalyst loadings. Applying first row transition metals to reactions such as Suzuki-Miyaura cross-coupling (SMC) require unique systems tailored to first row transition metals and guided by an understanding of their chemistry.

Recently, the Diao group at New York University applied an alcohol-appended diphenylphosphine ligand (ProPhos) to enable highly efficient cross-coupling of challenging heteroaromatic substrates. The development of this ligand was facilitated by mechanistic studies into the “Ni-oxo” transmetalation pathway, the formation of which comprises the turnover-limiting step in simple Ni-phosphine systems such as Ph₂PMe. By leveraging these mechanistic insights, Prof. Diao’s group was able to design a ligand system whereby a pendant hydroxyl group can interact with the boronic ester to direct the approach of the nucleophile and facilitate transmetalation (Figure 2). This provides an alternative reaction pathway to the relatively slower Ni-oxo formation, leading to enhanced reactivity and increased turnover.

The resulting ProPhos ligand system is able to achieve catalyst loadings as low as 0.1 mol%, a remarkable achievement for a nickel-catalyzed cross coupling reaction. The initial substrate scope explored coupling partners that have typically proven challenging for nickel, such as heterocycles containing pyridine, quinoline, pyrazole, pyrimidine, and 2-aminopyridine functionalities. NiCl₂•6H2O was also able to be employed as the metal source in these reactions, providing a much more stable and easy to work with starting material compared to Ni(0) sources such as Ni(COD)₂.

Altogether, the ProPhos ligand provides a promising start point towards the discovery and optimization of competent cross-coupling systems using nickel. ProPhos is available through the Strem Catalog (item # 15-0280).

References:

1. J. Am. Chem. Soc. 2024, 146, 6360.